Cyclopropyl-2-sulphanilamido-pyrimidines



United States Patent Olfice 3,441,560 Patented Apr. 29, 1969 3,441,560CYCLOPROPYL-Z-SULPHANILAMDO- PYRIMIDINES Markus Zimmermann, Riehen,Switzerland, assignor to Geigy Chemical Corporation, Ardsley, N.Y., acorporation of New York a No Drawing. Filed Mar. 14, 1967, Ser. No.622,899 Int. Cl. 'C07d 51/44; A61k 27/00 US. Cl. 260239.75 12 ClaimsABSTRACT OF THE DISCLOSURE BACKGROUND OF THE INVENTION Field of theinvention The invention concerns new sulphanilamide derivatives, aprocess for the production thereof, medicaments which contain the newcompounds and the use thereof.

Summary of the invention The invention provides, in a first aspect,novel sulfanilamido-pyrimidines of the formula:

wherein R represents hydrogen, halogen, a lower alkyl, lower alkoxy orlower alkylthio group, and one of R and R represents the cyclopropylgroup, and when R represents the cyclopropyl group, R representshydrogen, halogen, a lower alkyl, lower alkoxy or lower alkylthio group,and when R represents the cyclopropyl group, R represents hydrogen, alower alkyl or lower alkoxy group, as well as their salts with inorganicor organic bases; these novel compounds have an excellent antibacterialaction, which being practically harmless to mammals when used inantibacterially effective dosages, are therefore useful as antibacterialagents in the treatment of infectious diseases.

In a second aspect, the invention provides pharmaceutical compositionscontaining an antibacterially effective amount of a compound accordingto the invention and a pharmaceutically acceptable carrier therefor.

A third aspect of the invention provides for a method of treatinginfectious diseases in mammals by administering to an individualsuffering therefrom an antibacterially effective amount of a compoundaccording to the invention.

Detailed description of the invention and preferred embodiment In thecompounds of general Formula I, R R and R as alkyl groups are, e.g. themethyl, ethyl, propyl or the isopropyl group and, as alkoxy groups theyare, e.g. the methoxy group. In addition, as alkylthio groups, R and Rare, e.g. the methylthio or the ethylthio group.

As halogen atoms R, and/or R represent especially chlorine or bromine,but most preferably chlorine.

To produce these new compounds, a compound of the general Formula II:

xQsm-m-r is reacted, optionally in the presence of an acid bindingagent, with a compound of the general Formula III:

(III) N n j-NH-SOQX R12 R1 (IV) wherein R R R and X have the meaningsgiven in Formula I, if necessary, the group X of the above reactionproduct is converted into the free amino group, and/ or, if desired, areaction product containing halogen atoms, particularly chlorine atoms,as radicals R and/ or R is reacted with a metal compound of a lowalkanol or alkane thiol, or the reaction product is reduced until thehalogen atom R or R or the halogen atoms R and R is/ are eliminated and,if desired, the reaction product is converted into a salt with aninorganic or organic base. When A is the imino group and A is the directbond, Y is, e.g. a monovalent cation, particularly an alkali metal ion,or the normal equivalent of a polyvalent cation, and Z is a halogenatom, particularly a chlorine or bromine atom, also a cyanoamino ornitroamino radical or, if R and/or R is not an alkylthio group, Z is alow alkylsulphonyl radical. On the other hand, when A is the direct bondand A is the imino group, when Y is, e.g. a halogen atom, particularly achlorine atom, or an acyloxy radical, e.g. a radical of the generalFormula Nb:

and Z is a hydrogen atom, while X in this case is preferably not a freeamino group.

The reactions of compounds of the general Formula II with those of thegeneral Formula HI are performed, e.g. while heating in a suitableorganic solvent such as dimethyl forrnamide, acetamide, N,N-dimethylacetamide or dimethyl sulphoxide. When an acid is formed as liberatedcompound Y-Z; the reaction is performed in the presence of an acidbinding agent such as pyridine or tri methylamine in methylene chloride.In addition, free sulphonic acids (A is the direct bond, Y=OH) can bereacted with Z-acetamido-pyrimidine derivatives FNH, 2% DH CO) e.g. in alow alkanol.

The conversion of the group X of the reaction product of the generalFormula IV which may subsequently be necessary is a hydrolysis or areduction in the broadest sense depending on the type of this group.Radicals X which can be converted by hydrolysis into the amino groupsare e.g. acylamino radicals such as the acetamido into the amino groupare, e.g. the nitro group or substituted methylene amino radicals suchas the benzylidene amino radical, or the p-dimethylamino benzylideneamino radical. The hydrolysis of corresponding compounds of generalFormula IV to liberate the amino group can be performed e.g., in an acidmedium such as by heating in dilute methanolic hydrochloric acid, or itcan be performed under alkaline conditions, e.g. by means of 1 N to 2 Nsodium hydroxide solution at temperatures between 20-100. Radicals whichcan be converted by reduction into the amino group are, e.g. the nirtogroup or substituted azo radicals such as the phenylazo orp-dimethylamino-phenylazo radical, also, e.g. the benzyloxycarbonylaminoradical or the benzylidene amino radical. The reduction of these groupswhich can be reduced or cleaved by reduction can be performed in generalby catalytic means, e.g. with hydrogen in the presence of Raney nickelin an inert organic solvent, but also non-catalytic processes such asthe reduction of nitro groups and also azo groups by means of iron inacetic or hydrochloric acid can be used. A radical which can be reducedto the amino group is also the nitrilo radical which is bound by one ofits three valences to the henzene ring. In this case, the generalFormula II represents the divalent radical of Formula Ila:

wherein A and Y have the above-given meanings, which is bound to asimilar radical to form a derivative of azobenzene-4,4-disulphonic acidwhile forming a central azo group. This derivative is reacted with twomolecules of a pyrimidine derivative of the general Formula III.

Reactions of compounds of general Formula IV in which R and/or R arechlorine, with metal compounds, particularly alkali metal compounds suchas sodium compounds, of low alkanols are most easily performed using thealkanol concerned as solvent, while heating, e.g. at the boilingtemperature or at a raised temperature in a closed vessel. Also,dimethyl sulphoxide or dimethyl formamide can be used as solvent. Thesame solvents and the same temperatures are also suitable for thereaction of compounds of general Formula I wherein R and/ or R representhalogen, with alkylmercaptides, in particular with alkali metalalkylmercaptides. A halogen atom is eliminated by reduction,particularly a chlorine atom R and/ or R by, e.g. catalytichydrogenation in the presence of a base; for example palladium-bariumsulphate is used as catalyst and aqueous sodium hydroxide solution isused as a reaction medium. The compounds of general Formula IV used forthe reactions mentioned above can be obtained therefrom by conversion ofthe group X into the free amino group. Optionally, the replacement of achlorine atom R and/ or R by hydrogen can be performed in the same stepas the reduction of a group X suitable therefor, e.g. the nitro group.

To produce a first group of starting materials of the general FormulaIII wherein A is the direct bond, Z is a low alkylsulphonyl group or ahalogen atom, R and R are halogen atoms, alkoxy or alkylthio groups andR is the cyclopropyl group, for example, cyclopropyl malonic aciddialkyl esters, in particular the diethyl ester (cf. L. J.

Smith et al., J. Org. Chem. 15, 74 (1950)) are usedas startingmaterials. The esters mentioned are condensed with thiourea to form2-mercapto-5-cyclopropyl-4,6-pyrimidine diol which is methylated, e.g.with dimethyl sulphate in the presence of an acid binding agent, to form2- methylthio-5-cyclopropyl-4,6-pyrimidine diol. This latter is alsoobtainable in one stpe by condensation of the malonic acid estersmentioned with S-methyl isothiourea. Then, in the pyrimidine diolobtained, the hydroxyl groups are replaced by chlorine by treatment withan inorganic acid halide such as phosphorus oxychloride in the presenceof a tertiary organic base such as N,N-diethyl aniline and, if desired,the Z-methylthio-S-cyclopropyl- 4,6-dichloropyrimidine obtained isreacted with the metal compound of a low alkanol to form aZ-methylthio-S-cyclopropyl-4,6-dialkoxypyrirnidine. The corresponding 2-methylsulphonyl-S-cyclopropyl-pyrimidines, i.e.2-methylsulphonyl-S-cy.clopropyl-4,6-dichloropyrimidines and 2-methylsulphonyl S-cyclopropyl 4,6-dialkoxypyrimidines are obtained fromthe Z-methylthio compounds mentioned by means of an oxidising agent,e.g. peracetic acid.

On the other hand, the 2-methylthio-S-cyclopropyl-4,6- pyrimidine diolmentioned above can be converted into 5-cyclopropyl-2,4,fi-pyrimidinetriol (5-cyclopropyl barbituric acid) e.g. by boiling with 10% aqueouschloracetic acid or with concentrated hydrochloric acid, and the lattercompound can be modified by treatment with an inorganic acid halide inthe presence of a tertiary organic base, e.g. with phosphorusoxychloride and N,N- diethylaniline, into 2,4,6trichloro-5-cyclopropyl-pyrim idine. This compound which is alreadyembraced by the general Formula III can be used direct as startingmaterial provided allowance is made for the simultaneous formation ofisomeric N -(2,6-dichloro-5-cyclopropyl-4-pyrimidinyl)-sulphanilamide.Other compounds which can be used direct as starting materials are alsoobtained by converting, e.g. the trichloropyrimidine mentioned with alow alkylmercaptan in the presence of a low sodium alcoholate, into a2,4 dichloro-5-cyclopropyl-6-alkylthio-pyrimidine. In the reaction ofthese pyrimidines according to the invention, N-(4-chloro-S-cyclopropyl-G-alkylthio- 2-pyrimidinyl)-sulphanilamides areformed.

To produce a second group of starting materials of the general FormulaIII wherein A is the direct bond, Z is a halogen atom or a lowalkylsulphonyl group, R is a halogen atom or a low alkoxy or alkylthiogroup, R is the cyclopropyl group and R is hydrogen, a low alkyl oralkoxy group, e.g. known esters of ;9oxo-cyclopropane propionic acid,particularly the ethyl or methyl ester, or corresponding alkyl esters ofa-alkyl-fi-oxoor a-alkoxy-fioxocyclopropane propionic acids are used asstarting materials, and the esters mentioned are condensed with thioureato form 2-mercapto-6-cyclopropyl-, Z-mercapto- 5-alkyl-6 cyclopropylor2-mercapto-5 alkoxy-6-cyclopropyl-4-pyrimidinols. If S-alkyl thiourea isused as condensation component instead of thiourea, then instead of the2-mercapto-4-pyrimidinols the corresponding 2-alkylthio-4-pyrimidinolsare obtained. These intermediate products can be modified analogously tothe production of the first group of'starting materials, into2-alkyl-sulphonyl pyrimidines, or the 2-alkylthio-pyrimidines can beconverted by way of the 2-pyrimidinols into Z-halogenpyrimidines; inaddition, the hydroxyl groups in the 4- position can be modifiedanalogously into halogen or alkoxy groups. The following startingmaterials of the general Formula III, for example, are obtained:Z-methylsulphonyl-4 chloro-6-cyclopropyl, 2-methylsulphonyl-4-methoxy-6-cyclopropyl-, 2-rnethylsulphonyl-4 bromo-6- cyclopropyl-,2,4-dichloro-6-cyclopropyland 2,4-dibromo-6-cyclopropyl-pyrimidines andtheir 5-lower alkyl or 5-lower alkoxy derivatives as well as othercorresponding Z-alkylsulphonyl pyrimidines.

The a-alkyl-fi-oxo-cyclopropane propionic acid alkyl esters mentioned ascondensation components can be obtained, e.g. from ,B-oxo-cyclopropanepropionic acid alkyl esters and alkyl iodides in the presence of a lowsodium alcoholate, and the corresponding u-alkoxy18-oxocyclopropanepropionic acid alkyl esters can be obtained fromu-diazo-fi-oxo-cyclopropane propionic acid alkyl esters and a lowalkanol in the presence of copper and borotrifiuoride etherate.

To produce a third group of starting materials of the general Formula111 wherin A is the direct bond, Z is a low alkylsulphonyl group or ahalogen atom, R R and R can be hydrogen or low alkyl groups and one ofhalogen R and R is the cyclopropyl group, for example, a dioxo compoundof the general formula VI given below, or an acetal, enol ether, enamineor ketal of such a compound is condensed in the presence of an alkalineor acid condensing agent, with thiourea or S-alkyl-isothioureas. Theoptionally alkylated 2-alkylthio-5-cyclopropylor2-alkylthio-6-cyclopropylpyrimidines obtained with S-alkyl isothioureascan be oxidised direct, e.g. by means of peracetic acid, to thecorresponding 2-alkylsulphonyl pyrimidines of the general Formula III.The corresponding condensation products obtained from thiourea, i.e. theoptionally alkylated 2-mercapto-5-cyclopropylorZ-mercapto-6-cyclopropyl-pyrimidines are converted into thecorresponding 2-pyrimidinols, e.g. by boiling with aqueous chloraceticacid or with concentrated hydrochloric acid. These intermediate productsare then reacted with inorganic acid halides in the presence of tertiaryorganic bases, e.g. with phosphorus oxychloride and N,N-diethy1 aniline,to form the corresponding, optionally alkylated 2-halogen-pyrimidines,e.g. 2-chloro-5- cyclopropylor 2-chloro-d-cyclopropyl-pyrimidines aswell as their 4-, 5- and 6-lower alkyl or 4,6- and 4,5-di-lower alkylderivatives, which are embraced by general Formula III. The Z-mercaptopyrimidines mentioned above can also be alkylated however, i.e. reactedin the presence of an acid binding agent with low dialkyl sulphates oralkyl chlorides, whereupon, as described above, the 2-alkylthiocompounds obtained are oxidised to the 2-alkylsulphonyl compounds.Examples of such compounds of the general Formula III areZ-methylsulphonyl-S-cyclopropyland Z-methylsulphonyl-6-cyclopropylpyrimidine as well as their 4-, 5- and 6-lower alkyl or 4,6- and4,5-di-lower alkyl derivatives.

A fourth group of starting materials of the general Formula 111 whereinA represents the imino group and Z represents hydrogen and R R and Rhave the meanings given in Formula I, are obtained, e.g. from the2-alkylsulphonyl compounds by reacting them with ammonia. They can alsobe obtained in another way, however, by reacting guanidine with alkylesters of cyclopropyl malonic acid, B-oxo-cyclopropane propionic acid,a-alkybfloxocyclopropane propionic acids or a-alkoxy-fi-oxo-cyclopropanepropionic acids and converting the reaction products, e.g.Z-amino-S-cyclopropyl-4,6-pyrimidine diol, 2- amino-6-cyclopropyl-4pyrimidinol, 2-amino-5-alkyl-6- cyclopropyl-4-pyrimidinols or2-amino-S-alkoxy-6-cyclopropyl-4-pyrimidinols, with phosphorusoxychloride into 2-amino-5-cyclopropyl-4,6 dichloropyrimidine, 2-amino-4-chloro-6-cyclopropyl pyrimidine, 2-amino-4-chloro-5-alkyl-6-cyclopropyl pyrimidines or 2-amino-4-chloro-5- alkoxy 6cyclopropyl-pyrimdines, respectively. Corresponding low alkoxyoralkylthio-pyrimidines can be produced again from these substitutedchloropyrimidines with sodium and a low alkanol or alkane thiol.

In addition, the substituted 2-arnino-pyrimidines can be coverted withnitric acid into corresponding Z-nitroaminopyrimidines which form afifth group of starting materials of the general Formula III.

An example of a sixth group of starting materials of the general FormulaIII, a substituted Z-cyanoaminopyrimidine, is obtained, for example, byreacting dicyan diamide with l-cyclopropyl-1,3-butane dione to form 2-cyanoamino-4 methyl 6cyclopropyl-pyrimidine. Other compounds of thistype can be produced analogously.

A compound of the general Formula I is produced by a second processaccording to the invention by reacting a compound of general Formula V:

HO X wherein X has the meaning given in Formula 'II, with a compound ofthe general Formula VI:

R (VI wherein R represents hydrogen or a lower alkyl group, R representshydrogen, a lower alkyl group or the cyclopropyl group, R; has themeaning given in Formulas I and X that in Formula II, one of R and Rbeing the cyclopropyl group, if necessary, modifying the substituent Xin the reaction product of general Formula VII into the free amino groupand, if desired, converting the reaction product into a salt with aninorganic or organic base.

The condensation of fi-dioxo compounds of the general Formula VI orderivatives thereof with compounds of the general Formula V isperformed, e.g. with the aid of alkali metal alcoholates, e.g. sodiummethylate or sodium ethylate, in the corresponding low alkanols assolvent, while heating, e.g. at the boiling temperature of the alkanols.The alkali metal compounds of B-dioxo compounds are formed asintermediates. Condensations with diketones can also be performed, e.g.in glacial acetic acid or in alkanolic hydrochloric acid.

Examples of starting materials of the general Formula VI are derivativesof fi-oxo-cyclopropane propionaldehyde, e.g. enamines such as1-cyclopropyl-3-d'imethylamino-Z-propen-l-one and fl-diketones such asl-cyclopropyl-1,3 butane dione, l-cyclopropyl-l,3-pentane dione or1-cyclopropyl-1,3-hexane dione. These fl-diketones can be produced, e.g.from cyclopropyl methyl ketone with low alkane carboxylic acid alkylesters in the presence of a condensing agent such as sodium hydride.They can also be obtained in a two-step process by condensing sodium ormagnesium compounds of corresponding alkanoyl acetic acid alkyl esterswith cyclopropane carbonyl chloride to form diacylacetic acid alkylesters and hydrolysing and decarboxylating the compounds obtained in anaqueous or aqueous/organic medium. The enamine mentioned,1-cyclopropyl-3-dimethylamino-2-propen-1- one, can be produced fromcyclopropyl methyl ketone and bisdimethylamino methoxymethane inethanol.

The free sulphaguanidine (N -guanyl-sulphanilamide) is particularlysuitable as starting material of the general Formula V, but also othercompounds which contain, as radical X, one of the groups mentioned abovewhich can be converted by hydrolysis or hydrogenolysis into the aminogroup, can be used. "In particular, those compounds which occur asintermediate products in the production of sulphaguanidine, can be used.

A compound of general Formula I can be obtained by a third processaccording to the invention by reacting a compound of general Formula Vwherein X has the meanwherein R represents hydrogen, a lower alkyl groupor the cyclopropyl group, and R has the meaning given in Formula I, oneof R and R being the cyclopropyl group,

or with a lower dialkyl ester of cyclopropyl malonic acid, to form acompound of the general Formula IX:

H (XI) wherein R represents hydrogen, a lower alkyl group, thecyclopropyl group or the hydroxyl group, R has the meaning given inFormulas I and X that in Formula II, one of R and R being thecyclopropyl group, and treating the reaction product of general FormulaIX wherein R may be a hydroxyl group, with an inorganic acid halide tointroduce one or two halogen atoms instead of one or two hydroxylgroups, if desired reacting the reaction product with a metal compoundof a low alkanol or alkane thiol or reducing it to eliminate the halogenatoms(s) and also, if necessary, modifying the group X of the reactionproduct into the free amino group and, if desired, converting thecompound obtained into a salt with an inorganic or organic base.

The condensation according to the invention is performed, for example,with the aid of alkali metal alcoholates, e.g. sodium methylate orsodium ethylate, in the corresponding low alkanols as solvents whileheating, e.g. at the boiling temperature of the alkanols. The alkalimetal compounds of the fi-oxo esters are formed as intermediates.Insofar as such compounds result in the production of these substances,e.g. in the condensation of the cyclopropyl methyl ketone in thepresence of sodium hydride with diethyl carbonate to formfi-oxo-cyclopropane propionic acid ethyl esters, they can be used directin the condensation according to the invention instead of the freestarting materials and separate alkaline condensing agent.

Low alkyl esters, particularly methyl or ethyl esters, of compounds ofgeneral Formula VIII or of cyclopropyl malonic acid can be used asstarting materials for the process according to the invention. Thoseprocesses for the production of such compounds which are not describedin the literature have already been discussed at the end of the firstprocess according to the invention. Examples of low alkyl esters of thegeneral Formula VIII are the methyl or ethyl esters ofS-oxo-cyclopropane propionic acid as well as its a-methyl, a-ethyl,a-propyl, aisopropyl, a-methoxy, oc-BthOXY, a-propoxy or a-isopropoxyderivatives and, also, corresponding low alkyl esters ofa-cyclopropyl-B-oxo-butyric acid or of OL-CYCIOPI'OPYI- fi-oxo-valericacid.

The free sulphaguanidine (N -guanyl-sulphanilamide) is particularlysuitable as starting material of the general Formula V, but alsocompounds can be used which contain, as radical X, one of the groupsmentioned above which can be converted into the amino group byhydrolysis or hydrogenolys'is. Particularly those compounds can be usedwhich occur as intermediate products in the production ofsulphaguanidine.

. To further modify reaction products of the general Formula IX whichcontain one or two hydroxyl groups in the 4- or 4- and 6-position of thepyrimidine ring, these compounds are first converted by treatment withan inorganic acid halide in the presence of an acid binding agent, e.g.with phosphorus oxychloride and N,N-diethyl aniline, into thecorresponding 4-halogen or 4,6-dihalogen compounds. The further reactionof the latter compounds to introduce low alkoxy or alkylthio groups orhydrogen '8 into the 4 or 4- and 6-position of the pyrimidinyl radicaland also any conversion of the radical X into the free amino group havebeen discussed at the end of the first process according to theinvention.

If desired, the compounds of general Formula I obtained by the processesaccording to the invention are then converted'into their salts withinorganic or organic bases. These salts are produced, e.g. by reactingthe compounds of general Formula I with the equivalent amount of a basein a suitable aqueous/ organic or organic solvent such as methanol,ethanol, ether, chloroform or methylene chloride.

Instead of the free compounds of general Formula I, their salts withbases can be used as medicaments. Suitable salts are those which inthemselves have no physiological properties in the usual dosages. Also,it is of advantage if the salts to be used as medicaments crystallisewell and are not or are only slightly hygroscopic. Suitable salts are,e.g. sodium, potassium, magnesium, calcium and ammonium salts as well assalts with ethylamine, dimethylamine, diethylamine, triethylamine,ethylenediamine, choline, benzylamine, dibenzylamine, pyridine,piperidine, morpholine, N-ethyl piperidine, aminoethanol,diethylaminoethanol, diethanolarnine, triethanolamine and 1-(2-hydroxyethyl) piperidine. I

The new sulphanilamide derivatives corresponding to the generalFormula Iare suitable for the preparation of medicaments for internal or externaluse, e.g. for the treatment of infections by gram positive bacteria suchas staphylococci, streptococci, pneumococci as well as by gram negativebacteria such as Salmonella typhi, Escherichia coli and Klebsiellapneztmoniae.

The new active substances are administered orally and parenterally. Thedaily dosages of the free bases or of of pharmaceutically acceptablesalts thereof vary between and 5000 mg., preferably 300 to 5000 mg., foradult patients. Suitable dosage units such as tablets or ampoulespreferably contain 100 to 700 mg., preferably to 700 mg., of an activesubstance according to the invention or a pharmaceutically acceptablesalt thereof. Also corresponding amounts of forms not made up intosingle dosages such as syrups, ointments or powders can be used.

Dosage units for oral administration preferably contam between 60% and90% of a compound of the general Formula I or a pharmaceuticallyacceptable salt thereof as active substance. They are produced bycombining the active substance with, e.g. solid pulverulent carrierssuch as lactose, saccharose, sorbitol, mannitol; starches such as potatostarch, maize starch or amylopectin, also laminaria powder or citruspulp powder; cellulose derivatives or gelatlne, optionally with theaddition of lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights, to form tablets.

Ampoules for parenteral, particularly intramuscular, administrationpreferably contain a water soluble salt of an active substance in aconcentration of, preferably,

-10%, in aqueous solution, optionally together with suitable stabilisingagents and buffer substances.

The following prescription further illustrates the production oftablets:

50.000 kg. of N -(6-cyclopropyl 2-pyrimidinyl)-sulphanilamide are mixedwith 2.000 kg. of dried potato starch. The mass obtained is moistenedwith 1.200 kg. of stearic acid in 4 litres of ethanol and the whole ismixed for 15 minutes. 1.200 kg. of gelatine in 16 litres of distilledwater are added and the mass is kneaded for 20 minutes. When it isevenly moistened, it is granulated through a sieve (25 meshes/ sq. cm.)and dried. The dried granulate is again sieved (50 meshes/sq. cm.) andthen mixed for 1 hour with 4.000 kg. of potato starch, 1.200 kg. oftalcum and 0.400 kg. of sodium carboxymethyl cellulose. The massobtained is pressed into 100,000 tablets each weighing 600 mg. andcontaining 500 mg. of active substance.

The following examples further illustrate the production of the newcompounds of general Formula I and of hitherto undescribed intermediateproducts, but they in no way limit the scope of the invention. Thetemperatures are given in degrees centigrade.

EXAMPLE 1 (a) 2.53 g. of sodium are dissolved in 60 ml. of dry ethanol,8.75 g. of thiourea and 15.6 g. of fi-oxo-cyclopropane propionic acidethyl ester are added and the mixture is refluxed and stirred for 7hours at a bath temperature of 80-85 Without isolating the6-cyclopropyl-2- mercapto-4-pyrimidinol (6-cyclopropyl-2-thiouracil),first 20 ml. of water and then, dropwise, 9.3 ml. of dimethyl sulphateare added direct to the still hot mixture. The reaction is exothermic sothat the addition of dimethyl sulphate brings the reaction mixture tothe light boil. On completion of the addition, boiling is continued for15 minutes and then the opaque solution is filtered and concentrated todryness under vacuum. The residue is dissolved in 90 ml. of water, thepH is adjusted to 9 with a little 2 N sodium hydroxide solution and thesolution is extracted twice with ether. The aqueous phase is acidifiedwith N hydrochloric acid to pH 1-2, stirred for 1 hour while coolingwith ice and then the 6-cyclopropyl-2-methylthio-4-pyrimidinol isfiltered otf under suction; it melts at 196-198".

The 6-cyclopropyl-2-methylthio-4-pyrimidinol is also obtained when 16.7g. of S-methyl-isothiourea sulphate in 40 ml. of dry methanol arereacted with a solution of 5.06 g. of sodium in 40 ml. of dry methanol,then 15.6 g. of B-oxo-cyclopropane propionic acid ethyl ester are addedwhile cooling with ice and the Whole is stirred for 20 hours whilecooling with ice and then for 4 days at 20-25 The reaction mixture isconcentrated to dryness under vacuum and the residue is dissolved in 100ml. of water. The solution is acidified to pH 1 by the addition of 5 Nhydrochloric acid, the precipitated 6-cyclopropyl-2-methylthio-4-pyrimidinol is filtered otf under suction, washed with alittle water and dried; it melts at 196-199.

(b) A mixture of 34 ml. of phosphorus oxychloride, 6.8 ml. ofN,N-diethyl aniline and 6.8 g. of 6-cyclopropyl-2-methylthio-4-pyrimidinol is stirred for 45 minutes at a bathtemperature of 90. The pale brown solution is then concentrated todryness in vacuo, ice is added to the oily residue which is thenextracted three times with ether. The ether extracts are then washedfirst with ice cold 5% sodium bicarbonate solution, then with saturatedsodium chloride solution and dried over sodium sulphate. Afterevaporation of the ether, the crude 6- cyclopropyl-4-chloro 2methylthio-pyrimidine remains which is sufficiently pure for thefollowing reactions.

(c) 1.9 g. of 6-cyclopropyl-4-chloro-2-methylthiopyrimidine aresprinkled into 21 ml. of a stirred solution of peracetic acid in glacialacetic acid at 7-9. The exothermic reaction causes a rise of intemperature. Stirring is continued for 10 minutes at an innertemperature of 30 and then for 3 minutes at 80. The reaction mixture isthen concentrated under 12 torr, Water is added to the concentrate andit is cooled with ice for 2 hours. The crude sulphone, 6-cyclopropyl-4-chloro 2 methylsulphonyl-pyrimidine, is filtered off under suction; itthen melts at 102-104".

(d) 1.5 g. of the crude sulphone are stirred with 2.52 g. ofsulphanilamide sodium salt in 14 ml. of dimethyl formamide at a bathtemperature of 80 for hours. The dimethyl formamide is then distilledoff under high vacuum and the residue is dissolved in Water. The pH ofthe solution is adjusted to 8-9 by the addition of solid carbonic acidand, after stirring for 1 hour in an ice bath, the precipitatedsulphanilamide is filtered off under suction. The pH of the filtrate isadjusted to 5-6 with 5 N hydrochloric acid and, after cooling for 1 hourin an ice bath, the crude product is filtered off. Pure N -(6cyclopropyl 4 chloro 2 pyrimidinyl)- sulphanilamide is obtained bycrystallisation from iso- 10 propanol/water (2:1). It melts at 167-168with gas development.

(e) In the compound obtained according to l d), the chlorine atom may bereplaced by an alkoxy group in the following manner: 1 g. of N-(6-cyclopropy1-4- chloro-2-pyrimidinyl)-sulphanilamide is added to asolution of 0.23 g. of sodium in 20 ml. of dry methanol and the mixtureis boiled for 20 hours while stirring. The methanol is then distilledoff and the residue is dissolved in water. After adding 5 N hydrochloricacid until the pH is 5, the crude product precipitates. It isrecrystallised from isopropanol/water and dried for 30 hours at under0.1 torr. The substance sinters slightly; it is mixed well once duringthe drying process. The N -(6-cyclopropyl-4-methoxy-2-pyrimidinyl)sulphanilamide melts at 140-141".

(f) Furthermore, in a compound obtained according to 1 d), the chlorineatom may be replaced by hydrogen in the following way: 3.25 g. of the N-(6-cyclopropyl-4- chloro-Z-pyrimidinyl)-sulphanilamide are suspended in500 ml. of water, 20 ml. of 1 N sodium hydroxide and 2 g. of a 5%palladium/ barium sulphate catalyst are added and the Whole ishydrogenated at 20 under normal pres sure. of the theoretical amount ofhydrogen has been taken up after 24 hours. The catalyst is filtered OEand washed with water and the filtrate is acidified to pH 5-6 with 5 Nhydrochloric acid. A precipitate is formed which is filtered off undersuction and recrystallised from aqueous ethanol. The crystals obtainedare dried in vacuo at 70, whereupon the pure N -(6-cyclopropyl-Z-pyrimidinyl)-sulphanilamide melts at 241-243 withdecomposition.

EXAMPLE 2 (a) 1.15 g. of sodium are dissolved in 50 ml. of dry methanoland 10.7 g. of anhydrous sulphag'uanidine are added. The mixture isbrought to the boil While stirring and then 7.8 g. of B-oxo-cyclopropanepropionic acid ethyl ester are added dropwise. The mixture is thenrefluxed for 18 hours. The reaction mixture is then cooled for 3 hourswith ice and the precipitated crude product is filtered off undersuction. The filter residue is dissolved in 50 ml. of water and thesolution is adjusted to pH 4-5 with glacial acetic acid. After coolingand stirring in an ice bath for 2 hours, the crude N -(6-cyclopropyl-4-hydroxy-2-pyrimidinyl)-sulphanilamide is filtered 01f under suction.

A further amount of the reaction product can be obtained from the abovemethanolic filtrate by concentrating the latter to dryness, extractingthe residue with aqueous sodium hydroxide solution at pH 10 andprecipitating the reaction product from the alkaline extract by theaddition of glacial acetic acid at pH 4-5.

On recrystallising twice from ethanol/water (1:1), pure substance whichmelts at 226-228 is obtained.

(b) 1 g. of N -(6-cyclopropyl-4-hydroxy-2-pyrimidinyl)-sulphanilamide isadded to a mixture of 15 ml. of phosphorus oxychloride and 2 ml. ofN,N-diethyl aniline and the Whole is stirred for 2 hours at a bathtemperature of Excess phosphorus oxychloride is then distilled off under12 torr and the oily residue is poured into ml. of 2 N ice cold sodiumcarbonate solution. The whole is stirred for 2 hours at 20-25 and thenextracted with ether. The pH of the aqueous phase is adjusted to 3-4with 5 N hydrochloric acid and left to stand for a few hours at 4. Theamorphous precipitate is filtered 01f under suction, dried overphosphorus pentoxide and continuously extracted for 8 hours with hotbenzene. On concentrating the benzene extract, the crude N(6-cyclopropyl 4 chloro 2 pyrimidinyl)-sulphanilamide is obtained whichmelts at -162. Oncrystallising from benzene or from a mixture ofisopropanol/Water (2:1), the pure product is obtained which melts at167l68.

The substance is polymorphous. On a single crystallisation fromisopropanol/water, a melting point of 137-139 was observed. A subsequentcrystallisation of 1 1 this substance from benzene showed a meltingpoint of 167-168".

EXAMPLE 3 (a) 3.4 g. of 6-cyclopropyl-2-mercapto-4-pyrimidinol (producedaccording to Example 1, isolated by precipitation with N hydrochloricacid) are refluxed for 10 hours with a solution of 6.5 g. of chloraceticacid and 60 ml. of water. The reaction mixture is then cooled in an icebath and the precipitated crude 6-cyclopropyl uracil is filtered oilunder suction. It melts at 211-2l7 and is sufficiently pure for thefollowing reaction.

(b) 3.1 ml. of N,N-diethyl aniline are added to 15.5 ml. of phosphorusoxychloride and then 3.1 g. of crude 6- cyclopropyl uracil are sprinkledin. The mixture is stirred for 30 minutes at a bath temperature of 90.The dark brown solution is then concentrated under 12 torr while gentlyheating. The residue is poured onto ice and the mixture is extractedthree times with ether. The ether extract is washed once with water,dried with sodium sulphate and then concentrated. The crude6-cyclopropyl-2,4-dichloropyrimidine remains as an oil.

(c) 7.8 g. of sulphanilamide sodium salt and 3.1 g. of crude6-cyclopropyl-2,4-dichloropyrimidine in 15 ml. of dimethyl formamide arestirred for 1 hour at and for 14 hours at a bath temperature of 40. Themixture is then concentrated to dryness under about 0.1 torr and theresidue is dissolved in Water. The pH of the aqueous solution isadjusted to 8-9 by the addition of carbon dioxide. It is then cooled for1 hour in an ice bath and the excess sulphanilamide is filtered offunder suction. The pH of the filtrate is adjusted to 4-5 with 5 Nhydrochloric acid whereupon the brown crude product precipitates, firstin as greasy form which then crystallises. It is dried over phosphoruspentoxide and then extracted with boiling benzene in a Soxhletapparatus. The benzene extract is then extracted with 1 N sodiumcarbonate solution. 5 N hydrochloric acid is added to the aqueous/alkaline phase until the pH is 5-6 whereupon crystalline, white N -(6-cyclopropyl-4-chloro-2-pyrimidinyl) sulphanilamide precipitates. Thinlayer chromatography shows an R value of 0.53 (solvent:chloroform/methanol, 4:1; Merck Kieselget G; developer:p-dimethylaminobenzaldehyde). It is identical with the product obtainedaccording to Examples 1d and 2b.

EXAMPLE 4 (a) A solution of 5.3 g. of sodium in 50 ml. of methanol isstirred vigorously, refluxed and 10.1 g. of guanidine carbonate areadded in portions. The hot suspension is left to stand for 20 minutes,then filtered under suction and the residue is washed with dry methanol.The clear filtrate is stirred, refluxed and 15.6 g. ofB-oxo-cyclopropane propionic acid ethyl ester are added dropwise. The reaction mixture is then stirred and boiled for another 5 hours whereuponthe methanol is distilled off. The residue is dissolved in 30 ml. of hotwater and the pH of the solution is adjusted to 5-6 with glacial aceticacid. The reaction mixture is then left to stand for 16 hours at 4, theprecipitate is filtered off and washed with water, and the filtrate isdiluted with water. The crude 2-amino-6-cyclopropyl-4-pyrimidinolprecipitates. After recrystallisation from water, it melts at 202-203.

(b) 3.0 g. of the crude pyrimidinol obtained according to Example 4a areadded to a mixture of 20 ml. of phosphorus oxychloride and 4 ml. ofN,N-diethyl aniline and the mixture is heated for 45 minutes at 90.Excess phosphorus oxychloride is distilled off under vacuum, ice isadded to the brown residue and the suspension is extracted with ether.The ether extract is washed with a little water and dried over sodiumsulphate. After distilling off the solvent, crudeZ-amino-6cyclopropyl-4-chloropyrimidine is obtained.

(c) 7.1 g. of the crude chloride obtained according to Example 4b areadded to a solution of 2.3 g. of sodium in 110 ml. of dry methanol. Themixture obtained is stirred for 18 hours at a bath temperature of -90".The suspension is then concentrated in vacuo, the residue is stirredwith 40 ml. of water and the suspension is extracted with ether. Theether solution is dried over sodium sulphate and concentrated. Theresidue is crystallised from ethanol/ water and the crystals obtainedare dried over phosphorus pentoxide in vacuo at 20. The2-amino-4-methoxy-6- cyclopropyl-pyrimidine obtained melts at 72-74".

(d) 1.3 g. of Z-amino-4-methoxy-6-cyclopropyl-pyrimidine are dissolvedin 4 ml. of dry pyridine and, while stirring at 20, 2.07 g. ofp-chlorosulphonyl carbanilic acid methyl ester[(p-methoxycarbonylamino)-benzene sulphochloride] are added in portions.The reaction mixture is stirred for 25 minutes at 20 and for 1 hour at60. The brown reaction solution is then concentrated in vacuo. Theresidue is stirred in 40 ml. of 1 N sodium hydroxide solution for 1 hourat a bath temperature of -100. The opaque solution obtained is filteredand the pH of the filtrate is adjusted to 5-6 with 5 N hydrochloricacid. The crude product precipitates, it is filtered off under suction,washed with water, recrystallised from isopropanol/water and dried underhigh vacuum at 60. The N -(6-cyclopropyl-4-methoxy-2-pyrimidinyl)-sulphanilamide obtained melts at 141.

EXAMPLE 5 (a) 9.6 g. of sodium hydride are stirred with 35.2 g. ofacetic acid ethyl ester and 2 drops of dry ethanol are added. After afew minutes, development of hydrogen c-an be seen, whereupon a solutionof 16.8 g. of cyclopropyl methyl ketone in 50 ml. of dry ether is addeddropwise at 25-30". The reaction mixture, which gradually becomes moreand more of a slurry, is diluted with 20 ml. of dry ether, thesuspension is stirred for 14 hours at a bath temperature of 40-50 and isthen cooled to 20. 100 ml. of ether and 30 ml. of ethanol are thenadded, the reaction vessel is rinsed with nitrogen and a mixture of 80ml. of 5 N hydrochloric acid and 300 g. of ice cubes are added all atonce. Two phases are formed; the aqueous phase is separated and washedwith fresh ether. The combined ether extracts are then washed with adilute sodium hydrogen carbonate solution, and also with water, driedover sodium sulphate, distilled and fractionated. The1-cyclopropyl-1,3-butane dione obtained boils at 70-73/ 14 torr.

(b) 7.2 g. of the diketone obtained accordin to Example 5 a, 23 ml. ofn-amyl alcohol, 4.55 ml. of glacial acetic acid and 12.25 g. ofsulphaguanidine are mixed and stirred for 15 hours at a bath temperatureof -150. A dark yellow suspension is formed which is diluted with 5 ml.of n-amyl alcohol and then heated for another 5 hours. The reactionmixture is then concentrated in vacuo and the oil which remains isstirred with 50 ml. of 2 N sodium hydroxide solution. The precipitateformed, which consists of non-reacted sulphaguanidine, is filtered offunder suction and extracted a second time with 2 N sodium hydroxidesolution. The combined extract is washed with ether and the aqueousphase is acidified to pH 5-6 with 5 N hydrochloric acid. The crudeproduct precipitates. It is recystallised twice from acetic acid ethylester, the mother liquors being purified with ative charcoal. The pure N(6-cyclopropyl-4-methyl-2-pyrimidinyl)-sulphanilamide obtained melts at146-148.

EXAMPLE 6 (a) 4.45 g. of 2-methyl-isothiourea sulphate and 5.8 g. ofcyclopropyl malonic acid diethyl ester are added to a solution of 1.35g. of sodium in 35 ml. of dry methanol and the mixture obtained isstirred for 4 days at 30 while excluding moisture. It is thenconcentrated in vacuo. The residue obtained is dissolved in 20 ml. ofwater and the solution is acidified to pH 6 with 6 N hydrochloric acid.The crude Z-methylthio-5-cyclopropyl-4,6-pyrimidine diol precipitates;the suspension is left to stand for 8 hours,

the crude product is filtered ofi, Washed with water and dried in vacuoat 60.

(b) 9 g. of the crude product obtained according to Example 6a are addedto 63 ml. of phosphorus oxychloride while cooling with ice and 4.5 ml.of N,N-diethyl aniline are added dropwise to the mixture. The reactionvessel is then put into a bath which is heated to 90-100 within 15minutes, whereupon a clear solution is formed. The bath temperature ismaintained for 1% hours, then excess phosphorus oxychloride is distilledoff in vacuo and the residue is poured onto ice. The reaction mixture isextracted with ether, the ether extractis washed with water and driedover sodium sulphate. After evaporating ofi the ether, the crude2-methylthio-5-cyclopropyl-4,6- dichloropyrirnidine crystallises, M.P.65-70. Recrystallisation from petroleum ether raises the melting pointto 78-80.

(c) 8 g. of the methylthio compound obtained according to Example 6b areadded to 74 ml. of a 10% (percent by weight) of peracetic acid solutionin glacial acetic acid, the addition being made within 30 minutes at7-9. The reaction mixture is then stirred, first for 10 minutes at 20and then for 10 minutes at 80-90", after which it is concentrated invacuo. Water is added to the residue which is then filtered OE and,after drying over phosphorus pentoxide, it is recrystallised fromether/hexane. The pure 2- methylsulphonyl-S-cvclopropyl 4,6dichloropyrirnidine melts at 134-136".

(d) 2.30 g. of the product obtained according to Example 6c and 3.34 g.of sulphanilamide sodium salt in 20 ml. of :dry dimethyl formamide arestirred for 6 hours at a bath temperature of 80. The solvent is removedunder high vacuum, the residue is mixed with 20 ml. of water andacidified to pH 3-4 with 2 N hydrochloric acid. A greasy precipitatefirst forms which after some time solidifies. It is dissolved in aqueoussodium carbonate solution, the solution is filtered and the pH of thefiltrate is adjusted to 4-5 With 6 N hydrochloric acid. The crudeproduct precipitates and is recrystallised from aqueous ethanol. The N-(5-cyclopropyl-4,6-dichloro 2 pyrimidinyl)-sulphanilamide obtainedmelts at l93-195.

(e) In the compound obtained according to 6d, the chlorine atoms may bereplaced by hydrogen in the following manner:

3.1 g. of N 5-cyclopropyl-4,6-dichloro-2-pyrimidinyl)- sulphanilamideare dissolved in 1 litre of water and 50 ml. of l N sodium hydroxidesolution and, in the presence of palladium/barium sulphate catalyst, thesolution is dehalogenated with hydrogen under normal pressure at 20. Thehydrogenation mixture is filtered, washed with 50 ml. of water and thepH of the filtrate is adjusted to 5 with 6 N hydrochloric acid. Thesuspension formed is left to stand for some hours at 5, the precipitateis then filtered ofl under suction, washed with water and recrystallisedfrom aqueous ethanol. The pure N -(5-cyclopropyl-2-pyrimidinyl)-sulphanilamide obtained melts at 225-226.

EXAMPLE 7 (a) 182 ml. of dry ethanol are added to 16.8 g. of cyclopropylmethyl ketone. The mixture obtained is stirred and, at a temperature of65-70, a solution of 32.8 g. of bis-(dimethylamino)-methoxymethane (cf.H. Bredereck et al., Chem. Ber., 98, 1078 (1965)) in 122 ml. of dryethanol is added dropwise within 3 hours, whereupon the whole isrefluxed for 15 hours. The ethanol is then distilled off and the residueis fractionated. The pure l-cyclopropyl-3-dimethylamino-propen-l-oneboils at 100103/ 0.007 torr and, after solidifying, melts at 44-46.

(b) 7.1 g. of the ketone obtained according to Example 7a and 11 g. ofguanidine carbonate are stirred in ml. of ethylene glycol monoethylether and reacted for 16 hours at a bath temperature of 140-150. Thereaction mixture is cooled to 20, diluted with water and extracted threetimes rwith methylene chloride. The three extracts are washed, one afterthe other, twice with water, then combined and dried over sodiumsulphate. After distilling ofi the methylene chloride, crude,crystalline 2-amino-6- cyclopropyl pyrimidine remains which melts at135-137.

(c) 4.3 g. of the crude amine obtained according to Example 7b arestirred with 13 ml. of dry pyridine and 7.98 g. of N-acetyl-sulphanilylchloride are added in portions to the suspension obtained. The reactionis slightly exothermic and a yellow solution is formed. After stirringfor 18 hours at 20-25, the reaction mixture is diluted with 130 ml. ofwater, the pH is adjusted to 1 with 2 N hydrochloric acid and the crudeN -acetylN -(6-cyclopropyl-2-pyrimidinyl)-sulphanilamide is filtered offunder suction. It is washed with Water and dried in vacuo at It melts at250 with decomposition. The pure compound is obtained by recrystallisingonce from aqueous ethylene glycol monomethyl ether. It melts at 265(with decomposition).

(d) 7.9 g. of the acetyl compound described in Example 7c are hydrolysedfor 2 /2 hours with 84 ml. of 2 N sodium hydroxide solution at a bathtemperature of The solution is treated with active charcoal, filteredand the filtrate is acidified with 5 N hydrochloric acid to pH 5. Theprecipitated, crude N -(6-cyclopropyl-2-pyrimidinyl)-sulphanilamide isfiltered off under suction, washed with water and the crude product isrecrystallised from aqueous ethylene glycol monomethyl ether. It meltswith decomposition at 241-243 and is identical with the compoundproduced according to Example If.

EXAMPLE 8 (a) 2.68 g. of sodium are added to 37 ml. of dry methanol, thesolution obtained is vigorously stirred and brought to the boil. 5.05 g.of guanidine carbonate are then added to the reaction mixture, this isrefluxed for 20 minutes and the precipitate is filtered off undersuction. The filtrate is stirred, boiled and 10 g. of cyclopropylmalonic acid diethyl ester are added dropwise under an atmosphere ofnitrogen. After the reaction mixture has been refluxed for 20 hours, itis concentrated in vacuo and the residue obtained is dissolved in Warmwater. The solution is decloured with active charcoal and the filtrateis acidified with 5 N hydrochloric acid to pH 4. The precipitated, crude2-amino-5-cyclopropyl-4,6-pyrimidine diol is filtered off under suction,washed with water and dried in vacuo at 100; it melts at 260 (withdecomposition).

(b) 7.35 ml. of dry pyridine are added dropwise to 73 ml. of ice coldphosphorus oxychloride and then 7.3 g. of the pyrimidine diol obtainedaccording to Example 8a are added. The mixture is heated for 2 hours ata bath temperature of 100 and the brown solution obtained isconcentrated in vacuo. Ice is added to the residue and the pH isadjusted to 5 at 0 with 2 N sodium carbonate solution. The precipitateis filtered ofi under suction, dried in vacuo at 60 and digested threetimes with 100 ml. of warm ether each time. Recrystallisation fromether/ hexane yields pure 2-amino-5-cyclopropyl-4,6-dichloro-pyrimidinewhich melts at 166-167".

(c) 1.2 g. of sodium are added to 50 ml. of dry methanol and thesolution obtained and 3.55 g. of Z-amino-5-cyclopropyl-4,6-dichloropyrimidine are heated for 4 hours in anautoclave at The reaction mixture is concentrated in vacuo and theresidue is extracted with methylene chloride. After distilling off themethylene chloride an amorphous residue remains which is stirred WithWater for 1 hour. The c ude product obtained is filtered off and, afterdrying in vacuo at 30, recrystallised from hexane. The pure2-amino-5-cyclopropyl-4,6- dimethoxy-pyrimidine melts at 86-88".

(d) 1.45 g. of the amine obtained according to Example 8c are dissolvedin 3.8 ml. of dry pyridine and then 1.92 g. of N-acetyl-sulphanilylchloride are added while stirring. A yellow solution is immediatelyformed which is left to stand for 22 hours at 20. After adding 50 ml. ofWater and :5 N hydrochloric acid until the pH is 2, crude 1 N -acetyl-N-(5-cyclopropyl-4,o dimethoxy 2 pyrimidinyl)-sulphanilamideprecipitates.

(e) 4 g. of the crude, moist acetyl compound obtained according toExample 8d and 40 ml. of 2 N sodium hydroxide solution are heated for 2hours at a bath temperature of 100". A precipitate is formed which isdissolved by the addition of hot water. The hot solution is decolouredwith active charcoal, the active charcoal is filtered ofr under suctionand, after cooling the filtrate, the latter is adjusted to pH 4-5 with 5N hydrochloric acid. The mixture is cooled for 1 hour in an ice bath andthe precipitate is then filtered off under suction. Recrystallisation ofthe crude product from aqueous ethanol yields the pure N (5cyclopropyl-4,6-dimethoxy-2-pyrimidinyl) sulphanilamide which melts at220'222.

EXAMPLE 9 5.5 g. of N-(5-cyclopropyl-4-chloro-6-methoxy-2-pyrimidinyl)-sulphanilamide aredehalogenated analogously to Example It with hydrogen using 2 g. of 10%palladium charcoal as catalyst. The crude product is recrystallised frommethoxyethanol/water. The pure N -(5-cyclopropyl-6-methoxy-2-pyrimidinyl)-sulphanilamide melts at 242- 244.

EXAMPLE 10 (a) 8.3 g. of sodium and 190 ml. of dry ethanol are reactedanalogously to Example 1 with 13.7 g. of thiourea and 25.5 g. ofa-methyl-fl-oxo-cyclopropane propionic acid ethyl ester and the productis then methylated with 18.9 g. of dimethyl sulphate. The crude6-cyclopropyl-5-methyl- 2-methylthio-4-pyrimidinol obtained melts at201211 and is used direct for the following reaction.

(b) 16.7 g. of 6-cyclopropyl-S-methyl-Z-methylthio- 4-pyrimidinol arereacted according to Example 1b with 117 ml. of phosphorus oxychlorideand 8.35 ml. of N,N- diethylaniline, and the crude, oily6-cyclopropyl-4-chloro- 5-methyl-2-methylthio-pyrimidine is used forfurther reaction direct.

(c) 13.3 g. of the crude chlorine compound obtained according to b areoxidised analogously to Example 1c with 113 ml. of a 10% peracetic acidsolution in acetic acid. The crude6-cyclopropyl-4-chloro-5-methyl-2-methyl sulphonyl-pyrimidine melts at110113 and is used for further reaction direct.

(d) 12.3 g. of the crude sulphone obtained according to Example 10c arereacted analogously to Example 1d with 21.4 g. of sulphanilamide sodiumin 45 ml. of dry dimethyl formamide. The crude product obtained isrecrystallised from methoxyethanol/ water and the pure N (6cyclopropyl-4-chloro-5-methyl-2-primidinyl) sulphanilamide melting at208' (with decomposition) is obtained.

EXAMPLE 11 6 g. of N-(6-cyclopropylA-chloro-S-methyI-Z-pyrimidinyl)-sulphanilamide aredehalogenated with hydrogen analogously to Example If using 2 g. ofpalladium charcoal catalyst.

Crystallisation of the crude product from methoxyethanol/water yieldspure N -(6-cyclopropyl-5-methyl-2- pyrimidinyD-sulphanilamide, M.P.246248.

1 6 EXAMPLE 12 2.54 g. of sodium methylate and 5.35 g. of N-(6-cyclopropyl-4-chloro-5-methyl-2-pyrimidinyl) sulphanilamide in 30ml. of dry dimethyl formamide are heated for 63 hours at a bathtemperature of 50-60. After cooling, the pale brown coloured reactionmixture is diluted with 30 ml. of water and the pH is adjusted to 5-6with 2 N hydrochloric acid. After standing for 1 hour in an ice bath,the precipitate is filtered off and recrystallised once with alcohol andonce with water. The pure N -(6-cyclopropyl-4-methoxy-S-methy1-2-pyrimidinyl)-sulphanilamide melts at 211.5-213.5.

I claim:

1. A compound of the formula N R I j-NH-SOQNH: R3 N wherein R ishydrogen, halogen, (lower)alkyl, (lower) alkoxy, or (lower)alkylthio;one and only one of R and R is cyclopropyl; R when other thancyclopropyl is hydrogen, halogen, (lower)alkyl, (lower)alkoxy or (lower)alkylthio; and R when other than cyclopropyl is hydrogen, (lower)alkylor (lower)alkoxy.

2. A nontoxic pharmaceutical acceptable alkali metal, alkaline earthmetal, or organic amine salt of a compound according to claim 1.

3. A compound as defined in claim 1, wherein said halogen is chlorine orbromine.

4. A compound as defined in claim 1, wherein said halogen is chlorine.

5. A compound as defined in claim .1, wherein R and R are each hydrogenand R is cyclopropyl.

6. A compound as defined in claim 1, wherein R is chloro, R is hydrogenand R is cyclopropyl.

7. A compound as defined in claim 1, wherein R and R are each hydrogenand R is cyclopropyl.

8. A compound as defined in claim 1, wherein R is methyl, R is hydrogenand R is cyclopropyl.

9. A compound as defined in claim 1, wherein R is methoxy, R is hydrogenand R is cyclopropyl.

10. A compound as defined in claim 1, wherein R is chloro, R is methyland R is cyclopropyl.

11. A compound as defined in claim 1, wherein R and R are each chloroand R is cyclopropyl.

12. A compound as defined in claim '1, wherein R is hydrogen, R ismethoxy and R is cyclopropyl.

References Cited UNITED STATES PATENTS 2/1967 Sprague 260239.75

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,441,560 April 29, 1969 Markus Zimmermann It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 1, line 19, "antibacterial" should read antibacterial Column 3,line 4, cancel "into the amino group are, e.g. the nitro group" andinsert radical, or low alkoxycarbonylamino radicals, Column 4, line 7"stpe" should read step Column 5, line 7, "wherin" should read whereinline 66, "coverted" should read converted Column 6, line 31, "R shouldread R Column 12, line 33, "20 ml" should read 200 ml line 61, "ative"should read active Signed and sealed this 24th day of March 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Commissioner of Patents Edward M. letcher, Jr.

Attesting Officer

